Cis-platin (DDP) is one of the most widely used anti-neoplastic agents for the treatment of human cancer with activity against a broad spectrum of malignancies, including testicular, ovarian, head and neck, bladder, and some forms of lung cancer. In spite of its potency, the frequent development of resistance to this drug is proving to be a major obstacle to curative therapy.(1) DDP resistance is expressed co-dominantly and is phenotypically stable for long periods in the absence of selection.(2) Unlike cells selected with many antimetabolites and drugs that participate in the multiple drug resistance phenotype mediated by the MDR I gene(3), both in vitro and in vivo selection with DDP at clinically relevant intensities usually results in cells that are only two- to four-fold resistant to this drug.(4) The molecular basis of DDP resistance has not heretofore been understood. Factors that have been identified as capable of contributing to DDP resistance include diminished DDP uptake, elevated glutathionine or metallothioneins and enhanced repair of DDP-induced DNA adducts(2).
It is an object of the present invention to identify the gene or genes involved in the DDP-resistant phenotype. Once identified, it would be possible to exploit this information in the development of assays, and so forth, based upon knowledge of the identification and characterization of the expression product of that gene.